Aneuploidy is the state of having an abnormal number of chromosomes in the genome. Although aneuploidy is often associated with diseases such as cancer and neural degeneration, recent studies have also demonstrated aneuploidy to be a large-effect mutation that could produce dramatic phenotypic variation and enable cells to rapidly adapt to environmental stress. Intriguingly, frequent aneuploidy has been reported to associate with certain normal somatic cells, such as liver hepatocytes and neurons and neural stem cells. The goal of this R21 study is to explore the idea that aneuploidy may be a genetic mechanism contributing to behavioral diversity of neurons. Specifically, we will use in vitro culture and differentiation of mouse neural stem cells (NSCs) as the experimental model to gain a first insight into how aneuploidy impacts the neuronal cell growth and differentiation and what might be the underlying mechanism (e.g. via karyotype-mediated changes in the transcriptome and proteome). We will also investigate, in light of recent studies in unicellular organisms, whether neuronal aneuploidy may be induced by stress and/or provide phenotypic variation that enable evolutionary adaptation to stress conditions encountered by brain cells. Supporting the proposed experiments, we have developed an effective pipeline for the generation and isolation of aneuploid NSCs with homogeneous or heterogeneous karyotypes and established several methods for quantifying chromosome number and karyotyping of single or populations of cells. Our proposed study has the potential to shed light on the possible genetic mechanisms underlying neuronal complexity. The knowledge gained could advance the understanding of pathogenesis of brain disorders due to chromosome numerical abnormalities.